Single-pill low-dose triple combination therapy versus standard-dose monotherapy in patients with mild to moderate hypertension: results from two randomized clinical trials

Abstract Background Single-pill low-dose combination (LDC) antihypertensive therapy is emerging as an effective strategy for better blood pressure (BP) control. Purpose This study compared the efficacy of a single-pill LDC containing amlodipine 1.67 mg, losartan potassium 16.67 mg, and chlorthalidone 4.17 mg (LDC-ALC) with standard-dose monotherapy of amlodipine 5 mg (A5) or losartan potassium 50 mg (L50) for reducing systolic BP (SBP) in patients with mild to moderate hypertension. Methods The HM-APOLLO-301 (Study 301, May 2022–June 2023) and HM-APOLLO-302 (Study 302, March–December 2024) trials were multicenter, randomized, double-blind, active-controlled, parallel-group phase III clinical trials. Study 301 compared LDC-ALC with A5, and Study 302 compared LDC-ALC with L50. Participants (≥19 years) with 140 ≤ SBP 180 mmHg and diastolic BP (DBP) 110 mmHg following a 4-week placebo run-in were randomized to receive LDC-ALC (n=181) or A5 (n=180) for 8 weeks in Study 301 and LDC-ALC (n=125) or L50 (n=124) for 8 weeks in Study 302. The primary endpoint was SBP reduction from randomization to week 8. Non-inferiority was assessed using the upper limit of a one-sided 97.5% confidence interval (CI) for between-treatment differences with a noninferiority margin of 3 mmHg. If non-inferiority was demonstrated, superiority was evaluated. Results In Study 301, LDC-ALC was non-inferior to A5 in SBP reduction (-19.1 mmHg vs. -19.6 mmHg; difference: 0.5 mmHg, 97.5% CI, -∞ to 2.8 mmHg). DBP reductions were comparable (-8.9 vs. -9.7 mmHg; difference: 0.8 mmHg; 95% CI: -0.6 to 2.2, p=0.267). In Study 302, LDC-ALC was non-inferior to L50 for SBP reduction (-20.2 vs. -16.4 mmHg; difference: -3.8 mmHg; 97.5% CI, -∞ to -0.6 mmHg) and showed superior efficacy (-19.9 vs. -16.4 mmHg; difference: -3.4 mmHg; 95% CI, -6.6 to -0.2, p=0.037). LDC-ALC achieved greater DBP reduction (-9.8 mmHg vs. -7.4 mmHg; difference: -2.5 mmHg; 95% CI: -4.4 to -0.6, p=0.012). At 8 weeks, BP levels were significantly lower with LDC-ALC than with L50 treatment (131.6/83.1 mmHg vs. 135.2/84.7 mmHg), with SBP and DBP differences of -3.4 mmHg (95% CI -6.6 to -0.2, p=0.037) and -2.5 mmHg (95% CI, -4.4 to -0.6, p=0.012), respectively. The BP control rate (140/90 mmHg) at 8 weeks was comparable between LDC-ALC and A5 (57% vs. 60%, p=0.537) but significantly higher for LDC-ALC compared to L50 (64% vs. 51%, p=0.042). More participants achieved SBP 130 mmHg with LDC-ALC than with L50 (47% vs. 31%, p=0.011). Female participants showed greater BP reduction with LDC-ALC compared to L50. No serious adverse events related to LDC-ALC were reported. Conclusion LDC-ALC was as effective as standard-dose amlodipine monotherapy and showed superior efficacy over losartan monotherapy at 8 weeks without increased adverse events. These findings support LDC therapy as an effective initial strategy for hypertension management.SBP reduction from baseline to week 8